Control release formulation containing a hydrophobic material as the sustained release agent

ABSTRACT

The present invention is directed to a sustained release pharmaceutical composition in oral dosage form consisting essentially of a pharmaceutically effective amount of a medicament and a hydrophobic material in the absence of a lactose or hydrophobic carbohydrate polymer, said medicament being present in an amount greater than about 25% of the pharmaceutical composition and having a water solubility greater than about 1 gram per 10 mL of water at 25° C., said hydrophobic material having a melting point ranging from at least about 40° C. to about 100° C. at 1 atm pressure, and being present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition and in an amount less than the of the medicament, and said hydrophobic material not being present in coating of said pharmaceutical composition; said pharmaceutical composition being prepared by direct compression in the absence of or melting the hydrophobic material or the use of high shear mixer. The present invention is also directed to a method of preparing said pharmaceutical composition.

RELATED APPLICATION

The present application is claiming benefit of Provisional ApplicationU.S. Ser. No. 60/297,146 filed on Jun. 8, 2001.

FIELD OF THE INVENTION

The present invention relates to a controlled release formulation inoral dosage form, preferably in the form of a tablet, containing ahydrophobic material as the sustained release agent.

BACKGROUND OF THE INVENTION

It is of great advantage to both the patient and the physician thatmedication be formulated so that it may be administered in a minimumnumber of daily doses from which the drug is uniformly released over adesired extended period of time. This effect is accomplished usingsustained or slow release compositions. Sustained or slow releasecompositions containing pharmaceutical medicaments or other activeingredients are designed to contain higher concentrations of themedicament and are prepared in such a manner as to effect sustained orslow release into the gastrointestinal digestive tract of humans oranimals over an extended period of time.

Well absorbed oral sustained or slow release therapeutic drug dosageforms have inherent advantages over conventional, immediate releasedosage forms. The advantages include less frequent dosing of amedicament and resultant patient regime compliance, a more sustaineddrug blood level response, therapeutic action with less ingested drugand the mitigation of side effects. By providing a slow and steadyrelease of the medicament over time, absorbed drug concentration spikesare mitigated or eliminated by effecting a smoother and more sustainedblood level response.

For this purpose, a controlled release formulation has to meet somecriteria; namely, it must effect an uniform and constant dissolution ofthe drugs, and it must be effective for an extended period of time. Itis also important that such a formulation be simple to make, that themanufacturing process be reproducible and that the product produced bythe manufacturing process be uniform. Moreover, if different drugs areused as the active components in the sustained release formulation, itis important that the manufacturing process be easily adaptable toaccommodate these various drugs.

Various hydrophilic and hydrophobic materials, including polymers, havebeen utilized in preparing sustained release formulations. In addition,they have been prepared by various methods, such as solvent evaporation,heat melting, direct compression and wet granulation. Nevertheless, itis well known that the materials used for effecting the controlledrelease as well as the method of manufacture have a significant effecton the control release performance of the oral dosage form. For example,ethyl cellulose, which is a hydrophobic polymer has been used to effectcontrolled release of medicaments. However, the release profile issignificantly different when it is used as a coating material than whenused as a directly compressible powder. Moreover, when matrix typetablets are made with ethyl cellulose using wet granulation methods, therelease profile is significantly different from that exhibited bycontrolled release oral dosage forms prepared by using ethyl celluloseas a directly compressible powder or by using ethyl cellulose as acoating material. Furthermore, if the hydrophobic material is melted inthe process of making a sustained release pharmaceutical composition,its release profile is different from that of a controlled releasepharmaceutical composition prepared by a different method. Thesedifferences in release profile show that the pharmaceutical compositionsprepared by the various methods are not the same, but are different.

These differences in release profile are not unique for ethyl cellulosecontaining pharmaceutical compositions; the release profile ofpharmaceutical composition containing other hydrophobic material such aswaxes or higher fatty acids or alcohols, and the like, as the controlledrelease agent are dependent not only upon the identity of thehydrophobic material as controlled release agent, but also upon themethod in which the pharmaceutical composition is prepared.

Hydrophobic materials have been used to control the release ofmedicaments. For example, waxes and lipids have been used as coatingmaterial to retard the release of drugs. For instance, the manufacturerof COMPRITOL® 888 (glyceryl behenate), GATTEFOSSE, investigated theeffects of coating granules and spheres containing theophylline withCOMPRITOL® 888 as a hot melt coating using fluid bed equipment atdifferent concentrations. The wax coating levels of the spherules were2%, 6% and 10% by weight, respectively. The release profile in water wasdetermined. At 2% levels (w/w) of the wax, 85% of the theophylline wasreleased within one hour. However, at 6% levels of the wax, 55% of thetheophylline was released within the first hour, with 35% thereofreleased in 5 minutes, and at 10% levels (w/w) of the wax, 38% of thetheophylline was released within the first hour, with 28% thereofreleased in 5 minutes. Considering the number of steps used in preparingformulations of this type, this is not an efficient way to formulatecontrolled released products, and the present inventor sought to find amore efficient process to prepare a controlled release tablet containinga hydrophobic component as the sustained release agent. Moreover, thepresent inventor also sought to find a method of controlling the releaseof the drug without placing the wax in a coating, but by blending thehydrophobic material with the drug.

There has been a great deal of literature regarding the use of waxes incontrolled release compositions when mixed with medicaments. The commonmethods of manufacturing sustained release medicaments in oral dosageforms using waxes as the controlled release material admixed with themedicament are (a) melting the drug and wax together, then cooling andmilling the melt, and finally tableting after mixing with excipient; (b)using wet granulation techniques, employing an organic solvent as agranulating medium; (c) mixing the drug and waxes in a high shearmixture and using the heat produced during the processing to achieve ahomogenous mixture; and (d) using heat radiation to effect melting ofthe wax in the presence of the drug. All of these methods are cumbersomeand can be hazardous.

Most of these techniques use large amounts of waxes to achieve areasonable controlled release formulation, and the wax is usuallypresent in high concentrations, e.g., greater than 30% (w/w) of thedosage form and in a weight ratio greater than 1:1 relative to the drug.For example, Abdallah in Alex. J. Pharm. 1992, 6, 243–246, evaluatedthree chosen lipophilic polymers, Precirol® ATO 5 (glyceryl palmitostearate), Precirol® wL-2155 (glyceryl stearate) and Compritol® 888(glycerol behenate) for the preparation of ibuprofen prolonged releasecompositions. The tablets were prepared by melting the drug and otheringredients with the polymers, cooling the melt and compressing thecooled melt. He found that granules having a size of 200–315 micronsprepared with either of the three polymers in a concentration of either10 or 20% by weight did not exhibit a release retarding effect; thegranule formulations prepared with the above-identified lipids in theseamounts released the drug completely within 30 minutes. At 50% level ofCOMPRITOL® 888, however, the granules exhibited a somewhat suitablesustained release profile. However, making a tablet with such a largeamount of wax necessarily makes the tablet too large and thus moredifficult to swallow, especially for elder patients. The presentinventor thus searched for a means of preparing sustained releaseformulation containing considerably less hydrophobic material.

Perez, et al. in PRHSJ. 1993, 12, 263–267 investigated the effect ofvarying wax levels and methods of matrix formulation on drug release.The amount of drug in the formulation was held at 10% w/w, while the waxlevel was varied from 10% to 50% w/w. The drug formulations wereprepared by two different methods. In one method, designated thephysical method, the drug, wax and diluent were blended in a Turbulamixer by geometric dilution for 20 minutes and then the mixture wascompressed into a tablet. In the second method, designated the soliddispersion method, the wax was melted and the drug in varyingconcentrations was incorporated into the melted wax. The molten mixturewas allowed to cool until it solidified, and then the solidified masswas granulated through a Stokes oscillating granulator equipped withscreen No. 12. Perez, et al. found that tablets prepared by the physicalmethod having the same concentration of wax released the drug at afaster rate than the corresponding drug prepared by the solid dispersionmethod. Tablets prepared by the physical mixture system containing 30%(w/w) wax released about 79% of drug within about six hours, while intablets containing 50% (w/w) wax, the drug release was 50% after sixhours. On the other hand, tablets prepared by solid dispersioncontaining 30% (w/w) wax showed a drug release of 72% in six hours,while those tablets prepared by the same method containing 50% (w/w) waxreleased only 30% of the drug in six hours. Further, they showed that asatisfactory release profile was obtained when the ratio by weight ofdrug to waxy material was greater than 1:1, e.g., at least 3:1.

Moreover, Perez, et al. showed that at 10% levels of wax (w/w),regardless of which method was used, the release profile wasunsatisfactory; the sustained release formulation released about 80% ofthe drug in about 2 hours when prepared by either method.

The prior art showed that at levels of 30% or higher of the waxymaterial, acceptable sustained release profiles were obtained, but atlower levels, such as 10%, an unsatisfactory sustained release profilewas obtained. Thus, these prior art references teach away from preparinga sustained release formulation containing less than 30% wax.

Reilly, et al. in AAPS 1991 investigated the release profile ofacetaminophen at 10% level using glyceryl behenate at variousconcentrations, 10%, 30% or 50% in spheres and tablets, with the latterbeing prepared by direct compression or by wet granulation. Thereference discloses that simple incorporation of the glyceryl behanateinto the spheres did not provide slow release. In the tablets, however,a 10% wax did not provide any sustained release action, but at levels of30% and 50% by weight (that is, 3:1 or 5:1 weight ratio of glycerylbehanate to drug), the tablets exhibited sustained release action.Moreover, for the tablet formulations, as the amount of wax increased,the amount of sustained release action also increased.

Another investigator Terrier investigated the influence of glycerolpalmitostearate on the release of drug. He noted that a tabletcontaining sodium salicylate as the medicament and glycerolpalmitostearate as the excipient in 40% by weight, which was prepared bywet granulation methods, did not exhibit any sustained release. Forexample, 50% of the drug was released in water after 20 minutes.

The above methods used to prepare the pharmaceutical composition wereprepared by methods other than direct compression. However, even if theformulation were prepared by direct compression, the prior art showedthat at least 30% of the wax was required in the formulation to effectsustained release. For example, El-Sayed, et al. in S.T.P. Pharma.Sciences, 1996, 6, 398–402 prepared a formulation containing 50%theophylline and 30% glyceryl behenate, HPMC or carbopol, and theremainder excipient. Although the tablet so prepared exhibited sustainedrelease formulation, the present inventor searched for a sustainedrelease formulation containing even less than 30% (w/w) wax and a methodfor preparing same.

The present inventor has found a way to overcome the shortcomings of theprior art and achieve his objective. More specifically, the presentinvention provides a means of preparing controlled release dosage formsusing a simple manufacturing process such as direct compression whichinvolves compression of the various ingredients after a simple mixingprocedure. The present inventor has found that effective sustainedrelease formulations can be prepared in this way which incorporatessignificantly less hydrophobic material than that used heretofore.

SUMMARY OF THE INVENTION

The present invention is directed to a sustained release pharmaceuticalcomposition in tablet form comprising a pharmaceutically effectiveamount of a medicament and a hydrophobic material as the sustainedrelease agent, said medicament and hydrophobic material being present inthe core of the pharmaceutical composition, said core excluding polymercapable of swelling that causes tablet disintegration, includinghydrophobic carbohydrate polymer, and excluding high concentrations oflow molecular weight water soluble excipients, including lactose, saidmedicament being present in an amount greater than about 25% (w/w) ofthe pharmaceutical composition and having a water solubility less thanabout 1 gram per 10 mL of water at 25° C., said hydrophobic materialhaving a melting point ranging from at least about 40° C. to about 100°C. at 1 atm pressure, and being present in an amount effective tocontrol the release of the medicament, said hydrophobic material beingpresent in an amount ranging from about 3% to about 20% by weight of thepharmaceutical composition and in an amount by weight less than that ofthe medicament. It is preferred that the pharmaceutical composition isprepared by direct compression without melting the hydrophobic materialor the use of a high shear mixer. Although the pharmaceuticalcomposition may be prepared using wet granulation techniques, it ispreferred that it is not so prepared.

It is also directed to a method of preparing a sustained releasepharmaceutical composition in tablet form which comprises (a) blending amedicament and a hydrophobic material and optionally a lubricant andoptionally an excipient and optionally an adjuvant to form asubstantially homogenous and uniform blend, said mixture excludingpolymer capable of swelling that causes disintegration of the tablet andhigh concentrations of low molecular weight water soluble excipients,said medicament being present in an amount greater than about 25% byweight of the pharmaceutical composition and having a water solubilityless than about 1 gram per 10 mL of water at 25° C., said hydrophobicmaterial having a melting point ranging from at least about 40° C. toabout 100° C. at 1 atm pressure, and being present in an amount rangingfrom about 3% to about 20% by weight of the pharmaceutical composition;and (b) compressing the product of step (a) to form a tablet thereof,said pharmaceutical composition being formed without melting thehydrophobic material or utilizing a high shear mixer. Although thepharmaceutical composition may be prepared by wet granulation, it is notso preferred.

In another embodiment, the present invention is directed to a method ofadministering to a patient a medicament which comprises (a) preparing asustained release pharmaceutical composition in tablet form comprising apharmaceutically effective amount of a medicament and an effectiveamount of hydrophobic material to control the release of the medicamentfrom the pharmaceutical composition by direct compression without eithermelting said hydrophobic material or using a high shear mixer, saidpharmaceutical composition comprising a core comprising said medicamentand said hydrophobic material but excluding any polymer capable ofswelling that causes disintegration of the tablet and high concentrationof water soluble low molecular weight excipients, said medicament havinga water solubility less than about 1 gram per 10 mL of water at 25° C.and being present in the pharmaceutical composition in an amount greaterthan about 25% by weight and said hydrophobic material having a meltingpoint ranging from about 40° C. to about 100° C. and being present in anamount ranging from about 3% to about 20% by weight of thepharmaceutical composition and in an amount by weight less than that ofthe medicament and (b) administering the product of step (a) to saidpatient.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

As described hereinabove, an aspect of the present invention is directedto a sustained release formulation of a pharmaceutically activemedicament containing a hydrophobic material having a melting pointgreater than about 40° C. and less than about 100° C.

As used herein, the terms “drug” and “medicament” and “active substance”are used interchangeably. Moreover, the terms “controlled release” and“sustained release” are used interchangeably. By “sustained release”, itis meant, for purposes of the present application, that thetherapeutically active medicament or drug is released from theformulation at a controlled rate such that therapeutically beneficialblood levels (below toxic levels) of the medicament in an animal aremaintained over an extended period of time, e.g., providing 4, 8, 12, 16or 24 hours dosage form.

The controlled release formulation of the present invention is to beadministered to mammals in need of such treatment wherein the medicamentpresent in the formulation is administered in pharmaceutically effectiveamounts. By mammals, it is meant a vertebrae of the class mammalia, thatis, characterized by possession of hair and mammary glands. Examplesinclude, inter alia, dog, cat, horse, pig, goat, cow, humans and thelike. The preferred species of mammal to which the sustained releaseformulation of the present invention is to be administered is man.

The present pharmaceutical compositions comprises a formulation in unitdosage form. The term “unit dosage form”, as employed herein, refers toa physically discrete unit suitable as unitary dosage to mammals,including humans, with each unit containing a predetermined quantity ofactive material calculated to produce the desired effect in associationwith the hydrophobic material, the lubricant, if present, the excipientif present or other adjuvants, if present, as described herein.

The present formulation is applicable to a wide variety of drugs oractive medicaments suitable for use in sustained release formulation.

Representative medicaments include antacids, anti-inflammatorysubstances, coronary vasodilators cerebral vasodilators, psychotropics,antimanics, stimulants, anti-histamines, laxatives, decongestants,vitamins, gastrointestinal sedatives, anti-diarrhea preparations,anti-angina drugs, vasodilator anti-arrhythmics, anti-hypertensivedrugs, vaconstrictors and migraine treatments, anti-coagulants andanti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives,anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs,hyper- and hypoglycemia agents, thyroid and anti-thyroid preparations,diuretics, anti-spasmodics, uterine relaxants, mineral and nutritionaladditives, anti-obesity drugs, anabolic drugs, erythropoietic drugs,anti-asthmatics, expectorants, cough suppressants, mucolytics,anti-uricemic drugs and other drugs or substances acting locally in themouth, such as topical analgesics, local anesthetics, or combinationthereof and the like. The present formulation may contain more than oneactive ingredient.

The medicament used in the present invention has a low solubility inaqueous solution at 25° C. and 1 atm pressure. It has a water solubilityof less than about 1 gram per 10 ml of water at any pH existing in thegastrointestinal tract, typically between a pH of 1 and 7.5. However, ifthe drug is too insoluble in water then the sustained releaseformulation prepared therefrom is either too difficult to prepare ordoes not function effectively as a sustained release pharmaceuticalcomposition. Thus, the drug should have a solubility greater then about100 mg/liter of water at 25° C.

The drug has preferably a mean particle diameter from about 5 to about300 microns, more preferably from about 20 to about 200 microns and mostpreferably from about 30 to about 100 microns.

The preferred medicaments are theophylline, ferrous sulfate, niacin,giuaifenesin, clarithromycin, salts of valproic acid, especially GroupIA salts thereof e.g., Divalproex sodium, verapamil, dextromethorphan,diclofenac or pharmaceutically acceptable salts thereof, isosorbidemononitrate, levodopa, carbidopa, naproxen, and the like. As one ofordinary skill in the art is well aware, Divalproex is a mixture ofabout 50% (w/w) sodium or other Group IA metal salt of valproic acid andabout 50% (w/w) valproic acid.

The medicament is present in pharmaceutically effective amounts. It ispreferred that the medicament is present in amounts ranging from about25% to about 97% by weight of the pharmaceutical composition.

The pharmaceutical carrier of the present invention is comprised of thehydrophobic material. The hydrophobic material is the sustained releaseagent. The present pharmaceutical composition does not contain anyhydrophilic sustained release agents. The hydrophobic componentcomprises a water-insoluble wax-like material. The wax-like materialcomprises a solid generally insoluble substance having a waxyconsistency. It should, of course, be ingestible, pharmaceuticallyacceptable and non-toxic. Many such materials are known and include fatsand waxes. Wax, as used herein, is a low melting organic mixture orcompound of high molecular weight, and is a solid at room temperature,and is generally similar in composition to fat and oils except that itcontains no glycerides. Waxes include higher fatty acids, esters offatty acid, higher fatty alcohols and mixtures thereof. Fats, on theother hand, are glyceryl esters of higher fatty acids. All of these arehydrophobic materials as the term is used herein.

The hydrophobic material is present in sustained release retardingeffective amounts. It is present in the pharmaceutical composition ofthe present invention in amounts ranging from about 3% to about 20% byweight of the pharmaceutical composition, preferably from about 3% toabout 15% by weight more preferably from about 5 to about 15% and mostpreferably from about 7 to about 12% by weight of the pharmaceuticalcomposition. Thus, it is preferably present in less than 20% by weight.

The hydrophobic material may consist of one component or be a mixture oftwo or more hydrophobic components, as defined herein.

The hydrophobic material has a melting range above human bodytemperature, which is about 37° C. The hydrophobic material used in thepresent invention has a melting point greater than about 40° C., andmore preferably greater than about 45° C. However, it is critical thatthe hydrophobic material have a melting point above human bodytemperature. Waxes with melting points close to body temperature, suchas at 37° C., pose stability problems on storage as well as pose a riskof dose dumping. Thus, the minimum temperature of the hydrophobicmaterial is at about 40° C., i.e., a temperature above which theaforesaid problems do not manifest themselves. It is preferred that themelting point of the hydrophobic material ranges from about 40° C. toabout 100° C. and even more preferably from about 45° C. to about 90°C., especially more preferably from about 50° C. to about 80° C. andmost preferably from about 55° C. to about 75° C. It is important tonote that the presence of lubricants and/or other hydrophobic materialmay affect the melting range. However, the melting range of thehydrophobic material when associated with these other material in theformulation should not fall below body temperature.

It is preferred that the hydrophobic component has a mean particle sizefrom about 10 microns to about 200 microns. It is more preferred thatthe mean particle size ranges from about 20 to about 150 microns andmost preferably the mean particle size ranges from about 30 to about 100microns.

As indicated hereinabove, hydrophobic material useful in the presentinvention includes waxes and neutral fats. As will be describedhereinbelow, the hydrophobic material used in the present invention mustcontain at least 10 carbon atoms.

The useful waxes include those which are obtained from plant and/oranimal source or as a petroleum product, i.e., are obtained from naturalsources. Examples of this type of preferred waxes include carnauba wax,candelilla wax, spermaceti, beeswax, montan wax, hydrogenated vegetableoil, lecithin, hydrogenated cottonseed oil, hydrogenated tallow,paraffin wax, shellac wax, petrolatum, and the like as well as syntheticwaxes, e.g., polyethylene, and the like.

The hydrophobic materials also include fatty acid materials. The fattyacid materials preferably are of the class consisting of fatty acidshaving 10 to 40 carbons. The fatty acids may be straight chained orbranched, but it is preferred that they are straight chained. They maycontain no carbon-carbon double bonds, or they may contain carbon-carbondouble bonds. If they contain carbon-carbon double bonds, theypreferably contain 1, 2, 3, or 4 carbon-carbon double bonds and morepreferably 1 or 2 carbon-carbon double bonds. Examples include stearicacid, palmitic acid, lauric acid, eleostearic acids, a mixture ofstearic acid and palmitic acid, e.g., 85 wt % stearic acid and 15 wt %palmitic acid, and the like.

The fatty acid materials also include fatty alcohols having from 16 to44 carbon atoms. They also may be straight chain or branched, but it ispreferred that they are straight chained. They may be completelysaturated or contain carbon-carbon double bonds. If they containcarbon-carbon double bonds, they preferably contain 1, 2, 3, or 4carbon-carbon double bonds and more preferably 1 or 2 carbon-carbondouble bonds. Examples include stearyl alcohol, cetyl alcohol, palmitoland the like.

The fatty acid material also includes a fatty amine having 13 to 45carbons and a fatty amide having 11 to 45 carbons.

The hydrophobic material also includes neutral lipids. The neutrallipids are preferably of the class consisting of monoglycerides,diglycerides, triglycerides.

The monoglycerides, diglycerides and triglycerides are of the formula:

and R₄, R₅ and R₆ are independently alkyl or alkenyl, said alkyl andalkenyl groups having from 9 to 39 carbon atoms and wherein at least oneof R₁, R₂ and R₃ is other than hydrogen.

The alkyl groups and alkenyl groups of R₄, R₅ and R₆ may be branched andare preferably straight chained. The alkenyl groups may contain 1, 2, 3,or 4 carbon-carbon double bonds and if present, they more preferablycontain 1 or 2 carbon-carbon double bonds.

Examples include glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, polyglycolyzed glycerides and the like.

Besides glycerol esters, the hydrophobic material includes other fattyacid esters of polyhydric alcohols having two or more hydroxy groups inthe molecules which may be esterified to one or more fatty acids, asdefined herein, having the aforesaid characteristics describedhereinabove, such as the melting point in the range indicatedhereinabove. Examples of said polyhydric alcohols include alkyleneglycols, such as ethylene glycol and propylene glycol. It is preferredthat the polyhydric alcohols contain two or three hydroxy groups. Thepolyhydroxy alcohol is esterified to at least one fatty acid, as definedherein. The preferred fatty acids have the formula R₄COOH, wherein R₄ ineach fatty acid may be the same or different and is as definedhereinabove.

The hydrophobic material also includes pharmaceutically acceptable saltsof fatty acids, as long as the fatty acid has a melting point in therange indicated hereinabove. The fatty acid is as defined hereinabove.Examples include magnesium stearate and calcium and aluminum salts ofpalmitic acid, and the like.

It is preferred that the hydrophobic material is a fatty acid, or saltthereof, fatty alcohol, a wax or a neutral lipid. It is more preferredthat the hydrophobic material is a mono, di or triglyceride which isesterified to a fatty acid.

The most preferred hydrophobic materials are glyceryl behenate, glycerylpalmitostearte, glyceryl monostearate, polyglycolized glycerides,stearic acid, hydrogenated vegetable oil, cetyl alcohol or mixturesthereof. The most preferred hydrophobic material is glyceryl behenate.

The present pharmaceutical composition excludes in the core of thetablet in which the medicament and the sustained release agent describedhereinabove are present, any ingredient that can cause disintegration ofthe tablet. This includes any polymer, such as hydrophilic polymerscapable of swelling or hydrophobic carbohydrate polymers, as describedhereinbelow. Moreover, since high concentrations of low molecular weightwater soluble excipients can cause disintegration of the tablet, theyare also excluded in the core. As used herein, the term “highconcentration of low molecular weight water soluble excipients” refersto low molecular weight water soluble excipents being present inconcentrations greater than or equal to about 20% (w/w) of the tablet.In other words, the core of the pharmaceutical compositions of thepresent invention may include low molecular weight excipients as long astheir concentration is less than about 20% by weight of the tablet. Itis more preferred that the concentration thereof is less than about 10%by weight of the tablet (w/w).

The low molecular weight water soluble excipients are well known to oneof ordinary skill in the art. As defined herein, a “low molecular weightwater soluble excipient” refers to a water soluble excipient having amolecular weight of less than about 1000 daltons. Examples of lowmolecular weight water soluble excipients include lactose, sucrose,glucose, citric acid, sodium phosphate, buffering agents and the like.Thus, if the low molecular weight excipient has a solubility in watergreater than about 1 gm in 20 ml of water at 25° C. and 1 atmospherepressure and more preferably greater than about 1 gram in 10 ml of waterat 25° C. and 1 atmosphere pressure it is not present in the core of thetablet at high concentrations, as defined hereinabove. The water solublelow molecular weight excipient is present in less than about 20% byweight of the tablet and more preferably less than about 10% by weightof the tablet. By low molecular weight excipient, it is meant that anexcipient has a molecular weight of less than 1000 daltons.

Thus, the present compositions preferably do not contain any polymercapable of swelling or any low molecular weight excipients such aslactose in high concentration. Thus, the hydrophobic material excludeshydrophobic carbohydrate polymers, especially since they do not melt inthe aforesaid ranges. As defined herein hydrophobic carbohydratepolymers are hydrophobic cellulose derivatives in which the R moiety ofthe cellulose-R or cellulose-ROH or other R derivatives are either analiphatic acyl group of 2 to 100 carbons or larger or aliphatic alkylcontaining from 1 to 100 carbons or larger or chitin. Examples ofhydrophobic polymers which are excluded from the hydrophobic materialused herein are ethyl cellulose, propyl cellulose, cellulose acetate,cellulose propionate, cellulose acetate-butyrate, cellulose acetatepropionate, and the like. Moreover, the hydrophobic material excludesthe hydrated alkyl cellulose e.g., hydroxy alkyl cellulose.

Since the sustained release retarding agent of the pharmaceuticalcomposition of the present invention is a hydrophobic material, andexcludes polymers that swell, it excludes hydrophilic compounds as thesustained release agent, including hydrocolloids, as well as any gelforming substances, e.g., xanthan gum, guar gum,hydroxypropylmethycellulose, methacrylate or acrylate polymers and thelike. In addition, it excludes proteins.

Without wishing to be bound, it is believed that the controlled releaseof the medicament is achieved because of the presence of anon-disintegrating dosage which is rendered partially insoluble becauseof the wax. The wax helps control the release. By being insoluble inwater, the wax makes the pharmaceutical composition containing same atleast partially insoluble if not fully insoluble in water. If theexcipient is insoluble also, together the wax and the excipientstrengthen the tablet. The rate of dissolution or diffusion iscontrolled both by controlled erosion as well as controlled solubility.

On the other hand, any ingredient which can disrupt the tablet surfaces,such as polymers which can swell or disintegrating agents will weakenthe matrix (core) and cause the tablet to disintegrate. In fact, it isbelieved that the reason that in the prior art, high concentrations ofwax were used is because it contained swelling or disintegrating agents.

Other causes of disintegration includes high levels of solubleingredients, including low molecular weight water soluble excipientsdiscussed hereinabove.

However, polymers whether it be insoluble or soluble which do not swellare not excluded by the present invention. Moreover, water solubleexcipients which have molecular weights greater than 1000 daltons arealso not excluded and may be present in the tablet of the presentpharmaceutical composition, including the core thereof in concentrationsgreater than or less than 20% (w/w) by weight of the tablet. Thus, forexample, maltodextrin is water soluble and is a polymer, but it does notcause disintegration because it does not swell. It may be present in thetablet, including the core at concentrations greater than or less than20% by weight. Also polyethylene glycols with molecular weights greaterthan 1000 daltons may be present in the pharmaceutical compositions,including the core of the tablet in concentrations greater than or lessthan about 20% by weight of the tablet. These are completely watersoluble, but they can be used because they do not swell and the highmolecular weight PEG's retard disintegration.

Moreover, water insoluble excipients, may be present in concentrationsgreater than or less than about 20% of the tablet. These includemicrocrystalline cellulose, dicalcium phosphate and the like.

In the pharmaceutical composition of the present invention, thesustained release agent is the hydrophobic material. It is admixed withthe active medicament; it is present in the central core with thepharmaceutical composition. If the pharmaceutical composition contains acoating, the coating does not contain the sustained release agent.

Moreover, if the coating is present, it may contain swellable polymers,or disintegrating agents, including low molecular weight water solubleexcipients, since these are outside (on the surface) of the tablet.Thus, the polymers capable of swelling although cannot be present in thecore of the tablet may be present in the coating of the pharmaceuticalcomposition of the present invention. Moreover, the restriction on theconcentrations of the water soluble excipients refers to their presencein the core of the pharmaceutical compositions. There is no restrictionthereon if the water soluble excipients are present in the coating.However, it is preferred that the tablet does not contain a coating.But, if a coating is present, the water soluble low molecular weightexcipients and the swellable polymers are each preferably present inless than about 20% of the pharmaceutical composition and morepreferably in less than about 10% of the pharmaceutical composition.Further, if a coating is present, it is preferred that it does notcontain disintegrating agents and it is also preferred that it does notcontain water swelling polymers.

Without wishing to be bound, it is believed that the hydrophobicmaterial interacts with the medicament and retards it from beingreleased from the oral dosage form. More specifically, the hydrophobicsubstances used in the present invention are believed to form waterinsoluble matrices which remain intact for an elongated period of time,allowing leaching or diffusion of the drug at a controlled rate.

The inventor has found that the amount by weight of the hydrophobicmaterial used is less than that of the medicament. Thus, the weightratio of hydrophobic material to medicament is less than 1:1 by weight.It is preferred that the weight ratio of medicament to hydrophobicmaterial ranges from about 9:1 to about 5:4. Without wishing to bebound, it is believed that the smaller amount of hydrophobic materialmakes the dosage form more stable and physically stronger. Theconcentration of hydrophobic material used is reasonably small, allowingformation of very hard tablets, which can withstand various rigors. Itis also believed, without wishing to be bound, that the use ofhydrophobic material having melting point ranges higher than human bodytemperature also contributes to the stability of the dosage form andpredictability of the in vivo release of the medicament. Without wishingto be bound, it is believed that the heat generated during compressionmay cause softening of the wax, helping it to form a continuous matrixand particle coating of the formulation ingredients. The dosage formproduced by the process described hereinabove is believed, withoutwishing to be bound, to release the drug by erosion and diffusion froman essentially non-disintegrating matrix.

The present formulation also contains optional components. For example,although not necessary, in a preferred embodiment, the presentformulation additionally contains a lubricant that is typically used inthe pharmaceutical arts in oral tablets. As used herein, the term“lubricant” refers to a material which can reduce the friction betweenthe die walls and the punch faces which occurs during the compressionand ejection of a tablet. The lubricant prevents sticking of the tabletmaterial to the punch faces and the die walls. As used herein, the term“lubricant” includes anti-adherents. Examples of lubricants includestearate salts, e.g., alkali, alkaline earth, and transition metal saltsthereof, e.g., calcium, magnesium, or zinc; stearic acid, polyethyleneoxide, talc, hydrogenated vegetable oil, and vegetable oil derivatives,fumed silica, silicones, high molecular weight polyalkylene glycol,e.g., high molecular weight polyethylene glycol, monoesters of propyleneglycol, saturated fatty acids containing about 8–22 carbon atoms andpreferably 16–20 carbon atoms. The preferred lubricants are the stearatesalts, stearic acid, talc and the like.

When a lubricant is used, it is present in a lubricating effectiveamount of the lubricant. Preferably, the lubricant is present in amountsranging from about 0.1% to about 5% by weight and more preferably fromabout 1% to about 3% by weight of the tablet.

Another optional ingredient is an inert filler (excipient). The fillermay be substantially water-soluble or water insoluble. A filler is usedif needed or desired although not necessary for the present formulation.The fillers used in the present formulation are those typically used inthe pharmaceutical arts for oral dosage forms, such as tablets. Examplesinclude calcium salts, such as calcium sulfate, dicalcium phosphate,tricalcium phosphate, calcium lactate, calcium gluconate, and the like,glycerol phosphate; citrates; and mixture thereof, and the like.However, the inert filler of the sustained release formulation of thepresent invention may contain a pharmaceutically acceptable saccharide,including a monosaccharide, a disaccharide, or a polyhydric alcoholand/or mixtures of any of the foregoing. Examples thereof includesucrose, dextrose, polydextrose, maltodextrin, microcrystallinecellulose, fructose, xylitol, sorbitol, mixtures thereof and the like.The preferred excipient is maltodextrin.

Thus, another embodiment of the present invention comprises apharmaceutically effective amount of a medicament and a hydrophobicmaterial as the sustained released agent and maltodextrin, in theabsence of lactose and hydrophobic carbohydrate polymers, saidmedicament being present is an amount greater than about 25% (w/w) ofthe pharmaceutical composition and having a water solubility less thanabout 1 gram for 10 ml of water at 25° C. and 1 atm pressure and greaterthan about 100 mg/liter of water at 25° C. and 1 atm pressure, saidhydrophobic material having a melting point ranging from at least about40° C. to about 100° C. at 1 atm pressure and being present in an amounteffective to control the release of the medicament, said hydrophobicmaterial being present in an amount ranging from about 3% to about 20%by weight of the pharmaceutical composition and in an amount by weightless than that of said medicament.

It is also preferred that the pharmaceutical composition does notcontain lactose. Lactose is undesirable for several reasons. First, manypeople suffering from lactose intolerance will have difficulty indigesting an oral dosage form containing same. In addition, lactoseinteracts with various drugs containing certain functional group e.g.,amines, thereon. Although it may be used, it is preferred that thepharmaceutical composition of the present invention does not contain adisaccharide.

The filler, if present, is present in amounts ranging from but about 0%(but greater than 0) to about 72% by weight.

Other optional ingredients (adjuvants) that are also typically used inpharmaceuticals may also be present, such as coloring agents,preservatives (e.g., methylparabens), artificial sweeteners, flavorants,anti-oxidizing agents and the like. Artificial sweeteners include, butare not limited to saccharin sodium, aspartame, dipotassiumglycyrrhizinate, stevia, thaumatin and the like. Flavorants include, butare not limited to lemon, lime, orange and menthol. The colorantsinclude, but are not limited to various food colors, e.g., FD & Ccolors, such as FD & C Yellow No. 6, food lakes and the like. Examplesof anti-oxidants include ascorbic acid, sodium metabisulphite, and thelike. These optional ingredients, if present, are preferably present inamounts ranging from about 0.1% to about 5% by weight of the tablet andmost preferably less than about 3% (w/w) of the tablet.

However, it is preferred that the component in the greatestconcentration is the medicament. Moreover, it is preferred that the sumof medicament and hydrophobic material is greater than 45% by weight ofthe oral dosage form, and more preferably greater than about 60% byweight of the pharmaceutical composition.

The present formulation of the present invention is prepared by blendingthe medicament with the hydrophobic material and lubricant, if present,the filler, if present, and the adjuvants, if present. The ingredientsare mixed in a typical blender that is normally utilized in thepharmaceutical arts, such as a Hobart mixer, V-blender, a planetarymixer, Twin shell blender and the like. The ingredients are blendedtogether typically at about ambient temperature; no additional heatingis necessary, although slight modifications of temperature therefromcould be utilized. It is preferred that the blending be conducted attemperatures ranging from about 10° C. to about 35° C. The hydrophobicmaterial is not melted. Moreover, if the components are heated, theelevated temperature used in the present process is not evensubstantially close to the melting point of the hydrophobic material.The pharmaceutical composition of the present invention is not preparedby thermal infusion.

The ingredients in the formulation are preferably mixed together in alarge batch using techniques well known in the pharmaceutical arts andare intimately intermixed until the mixture is homogenous with respectto the drug. The term “homogenous” with respect to the drug is used todenote that the various components are substantially uniform throughoutthe invention, i.e., a substantially homogeneous blend is formed.

When the mixture is homogeneous the unit dosage form is prepared bytechniques known in the art. Thus, the mixture may be made into apellet, capsule, granule, pill, tablet or other unit dosage form usingconventional techniques known in the art.

The preferred unit oral dosage form is a tablet. The tablet can beprepared by the following procedure.

A unit dosage amount of the homogenous mixture is compressed into atablet form using a tablet machine typically utilized in thepharmaceutical arts. More specifically, the mixture is fed to the die ofa tablet press and sufficient pressure is applied to form a solidtablet. Such pressure can vary, and typically ranges from about 1,000psi to about 6,000 psi and preferably about 2,000 psi force. The solidformulation according to the present invention is compressed to asufficient hardness to prevent the premature ingress of the aqueousmedium into the tablet. Preferably, the formulation is compressed into atablet form which is of the order of 5–20 Kp and more preferably 8–20 Kpas determined by a Schleuniger hardness tested.

In a variation, all of the above steps are repeated, except that themixing is initially performed in the absence of a lubricant, if alubricant is to be added to the formulation. When the mixture ishomogeneous with respect to the drug, then the lubricant is added andthe mixing is continued until the lubricant, if present, may besubstantially evenly dispersed in the mixture. Then the mixing isterminated, and the mixture is immediately thereafter made into a unitdosage form. For example, it may be compressed into a tablet, asdescribed hereinabove.

Prior to the mixing step, the individual components may optionally bemilled, e.g., passed through a screen, sieve, etc. to reduce the size ofthe particles thereof. Alternatively, the substantially uniformlyblended mixture prior to the formation of the unit dosage form. Forexample, if it is a tablet, the mixture may be milled before thecompression step.

In the process described herein, unlike most methods, the hydrophobicmaterial is not melted, either separately from the other components ofthe pharmaceutical composition or with other components of thepharmaceutical composition. More specifically, in the process of thepresent invention, the components in the mixing step are not heated totemperatures at or substantially close to the melting temperature of thehydrophobic material. The present invention avoids the disadvantagesassociated with heat melting. First, heat labile compounds willdecompose in the molten hydrophobic material, e.g., wax. Further, it isexpensive and hazardous to adopt this molten wax technique to massproduction. Aside from the hazards of working with large quantities ofmolten material, there is the difficulty of working with the hardcongealed-medicament mixture which must be removed from the mixingvessel and sized. Additionally, the sizing of the hardcongealed-medicament mixture exposes the previously encased medicament,thereby detracting from its controlled release profile in subsequencedosage forms. A further outstanding disadvantage of the known art methodof preparing sustained release tablets, in particular, by the moltenheat process is that a high dosage drug cannot be easily prepared withsatisfactory release characteristics. The present inventor has foundthat he is able to prepare a pharmaceutical composition having excellentsustained release properties without melting the hydrophobic component,e.g., wax.

In addition, the present inventor has found that he is able to obtain asubstantially homogenous blend without subjecting the components to highshear mixing. Moreover, as indicated hereinabove, the methodologydescribed hereinabove is simple and economical and avoids the expenseassociated with the high shear mixer. Moreover, the present inventor hasfound that the present method provides a pharmaceutical composition withexcellent sustained release properties.

Moreover, the methodology used in the present invention to prepare thepharmaceutical composition does not utilize wet granulation. Thus, thepresent process does not have the disadvantages associated with wetgranulation. It avoids the hazards associated with the use of toxic orflammable solvents used in wet granulation methods.

This method used in the present process for preparing the sustainedrelease pharmaceutical composition of the present invention has severaladvantages. It is a simple and efficient method of manufacturing, moreso than if the composition were prepared by melting the hydrophobicmaterial or utilizing a high shear mixer. It overcomes the drawbacks offormulating with hydrophobic material, e.g., waxes, such as dimensionalstability, with respect to heat and abrasion. The hydrophobic materialis not melted or heated to just below melting temperatures such as byutilizing such techniques as radiation heating. In a preferredembodiment, the hydrophobic material is mixed with the other componentsat temperatures no higher than slightly elevated over room temperature,but substantially less than the melting temperatures of the hydrophobicmaterial. This technique minimizes the heat and energy in themanufacture of unit dosage forms of the present invention relative tothat used in the prior art, thereby making the present process moreefficient. In a preferred embodiment, no granulating solvents arerequired, thus in this embodiment, the present methods avoid the risksof toxicity and fires that are potentially present when using the wetgranulation methods in preparing sustained release pharmaceuticals.

After the unit dosage form, e.g., tablet, is formed, it may be coatedwith materials normally used in pharmaceuticals, if desired. If coated,the coating is prepared by techniques known in the art, but thehydrophobic material used as the controlled release agent is not presentin the coating. However, the formulation of the present invention ispreferably uncoated.

The unit dosage form prepared by the present invention has theproperties typically found in the pharmaceutical art. For example, ifthe unit dosage form is a tablet, the tablet product is obtained whichhas the desired hardness and friability typically found forpharmaceutical tablets. The hardness is preferably 5–25 Kp and morepreferably 8–20 Kp.

The present formulation in unit dosage form, e.g., tablet form, has anexcellent drug release profile. The release profile of thepharmaceutical formulation of the present invention is non-linear. Forexample, it has a predetermined controlled and sustained action and aregular delayed pattern so that the medicament is available over aperiod of up to 36 hours, depending upon the type of unit dosage formused, the precise size of the unit dosage form, the identity of theactive ingredient, aqueous solubility of the active ingredient, hardnessand the particular carrier composition. For example, in accordance withthe process of the present invention, a controlled releasepharmaceutical composition can be prepared wherein the release time is2–4 hours, 8 to 10 hours, 15–18 hours, 20–24 hours, etc. as desired.Furthermore, the release profile of each formulation is substantiallyuniform. Finally, if the oral dosage form is a tablet, the tabletsprepared in accordance with the present invention are hard and dense,have low friability and provide controlled and sustained release over anextended period. Solid dry forms prepared by the present invention arestable and their release rate does not change to any significant (ifany) extent over an extended period of storage.

The sustained release medicament is provided in solid form, convenientlyin a unit dosage form. It is preferred to provide the sustained releasemedicament in solid unit dosage form for oral administration, especiallyin tablet form. Preferably, it is intended to release thepharmacologically active ingredient slowly or according to a prescribedrate after ingestion within the body as the formulation progresses alongthe gastro-intestinal tract. In this regard, the gastro-intestinal tractis considered to be the abdominal portion of the alimentary canal, i.e.,the lower end of the esophagus, the stomach and the intestines.

The dosages of a formulation administered to a mammal in need thereofaccording to the invention, correspond to the normal dosages of theparticular active ingredient known to the skilled artisan. The preciseamount of drug administered to a patient will depend on a number offactors, including the age of the patient, the severity of the conditionand the past medical history, among other factors, and always lie withinthe sound discretion of the administering physician. For guideline as asuitable dosage, reference is made to the Physicians Desk Reference.

The pharmaceutical composition formed is preferably not multi-layered,but is only one layer.

Unless indicated to the contrary, all percentages are weight percentagesrelative to the oral dosage form. Moreover, unless indicated to thecontrary, the active ingredient, the hydrophobic material, and any otheroptional ingredients, e.g., lubricant, excipient, and other ingredientsare calculated on a dry weight basis, without reference to any water orother component present.

Moreover, as used herein, the singular shall refer to the plural andvice versa.

The following non-limiting examples further illustrate the presentinvention.

EXAMPLE 1

Ferrous sulfate (160 mg), glyceryl behenate (30 mg) and maltodextrin(110 mg) were thoroughly mixed together in a V blender for one hour andcompressed into a tablet using a rotary tablet press. The dissolutionwas determined using USP apparatus I in water. The release profile is asfollows:

Time (in hours) % Drug Release (w/w) 1 36 2 58 3 72 4 82

EXAMPLES 2–6

The following ingredients were mixed in a suitable blender for 1 hour.

Component EX. 2 EX. 3 EX. 4 EX. 5 EX. 6 Theophylline 600 mg 600 mg 600mg 400 mg 400 mg Glyceryl 60 mg 60 mg 60 mg 40 mg 50 mg behenateMaltodextrin — 29.5 mg 36.5 mg 23 mg 13 mg Fumed Silica — 3.5 mg 3.5 mg2.4 mg 2.4 mg Magnesium — 7 mg — 4.7 mg 4.7 mg stearate

The resulting mixture was compressed into a tablet using a rotary tabletpress. The dissolution of each formulation was determined using USPapparatus I in water. The release profile is as follows:

% Released (w/w) Time in Hours EX. 2 EX. 3 EX. 4 EX. 5 EX. 6 1 13 16 1217 14 3 24 25 22 29 26 5 32 36 30 38 33 7 38 42 34 45 39 9 — 47 37 — —12  — 54 44 — —

EXAMPLE 7

Clarithromycin (500 mg), glyceryl behenate (25 mg), silicifiedmicrocrystalline cellulose (220.15 mg), and maltodextrin (220.15 mg)were passed twice through a 40 mesh screen. The various ingredients weremixed in a double cone blender for 30 minutes. Magnesium stearate (14.7mg) was added to the mixture which was stirred for another fifteenminutes. The mixture was compressed into a tablet. The tablets werepunched using a 20×10 mm capsule shaped punch. The tablet contained 500mg clarithromycin and 980 mg total weight.

The dissolution was determined using USP apparatus I in acetate buffer,pH 5.0. The release profile was as follows:

Time (in hours) % Release (w/w) in acetate buffer pH 5.0 1 10.92 3 28.315 49.81 7 72.04 9 87.95 12 92.45

EXAMPLE 8

A tablet of divalproex sodium was prepared as follows:

Divalproex sodium (576.21 mg), glyceryl behenate (190 mg), polyvinylpyrrolidone (47.5 mg), dibasic calcium phosphate dihydrate (44.4 mg),silicified microcrystalline cellulose (44.4 mg) and aerosol (19 mg) werepassed twice through a 40 mesh screen. The various ingredients weremixed in a double cone blender for 30 minutes. Magnesium stearate (28.5mg) was added to the mixture and the mixture was stirred for anotherfifteen minutes. The mixture was compressed into a tablet. The tabletswere punched using a 20×10 mm capsule shaped punch. The tablet contained576.21 mg of diralproex sodium and 950 mg total weight.

The dissolution was determined using U.S.P apparatus I in water. Therelease profile was as follows.

Time (in hours) % Release in water (w/w) 1 25.87 3 39.30 5 47.46 7 55.02

The above preferred embodiments and examples were given to illustratethe scope and spirit of the present invention. These embodiments andexamples will make apparent to those skilled in the art otherembodiments and examples. The other embodiments and examples are withinthe contemplation of the present invention. Therefore, the presentinvention should be limited only by the appended claims.

1. A method of preparing a sustained release pharmaceutical compositionin oral dosage form which comprises (a) blending a medicament and ahydrophobic material and optionally a lubricant and optionally anexcipient and optionally an adjuvant polymer at a temperature below thatof the melting point of the hydrophobic material to form a substantiallyhomogenous and uniform blend, said medicament being present in an amountgreater than about 25% by weight of the pharmaceutical composition andhaving a water solubility less than about 1 gram per 10 mL of water at25° C. and 1 atm, and greater than about 100 mg per liter of water at25° C. and 1 atm, said hydrophobic material having a melting pointranging from at least about 40° C. to about 100° C. at 1 atm pressure,and being present in an amount ranging from about 3% to about 20% byweight of the pharmaceutical composition, and in an amount by weightless than that of the medicament; and (b) compressing the product ofstep (a) to form a tablet thereof; said pharmaceutical composition beingformed in the absence of thermal infusion or melting the hydrophobicmaterial or utilizing a high shear mixer or by heating to temperaturesslightly below the melting point of the hydrophobic material, saidcomposition excluding any ingredient in the core that causesdisintegration of the tablet.
 2. The method according to claim 1 whereina lubricant is additionally present.
 3. The method according to claim 1wherein the medicament, hydrophobic material and optionally an excipientand optionally an adjuvant are mixed together to form a substantiallyhomogenous and uniform first blend, and a lubricant in lubricatingeffective amounts is added to said first blend and is mixed therewith toform a substantially uniform and homogenous second blend, wherein thesecond blend is compressed to form a tablet.
 4. The method according toclaim 1 wherein an excipient is additionally present.
 5. The methodaccording to claim 3 wherein an excipient is additionally present. 6.The method according to claim 4 where the excipient is maltodextrin. 7.The method according to claim 5 where the excipient is maltodextrin. 8.The method according to claim 1 wherein the hydrophobic material ispresent in an amount ranging from about 5% to about 15% by weight of thepharmaceutical composition.
 9. The method according to claim 8 whereinthe hydrophobic material is present in an amount ranging from about 7%to about 12% by weight of the pharmaceutical composition.
 10. The methodaccording to claim 1 wherein the weight ratio of the medicament tohydrophobic material ranges from about 9:1 to about 5:4.
 11. The methodaccording to claim 1 wherein the melting point of the hydrophobicmaterial ranges from about 40° C. to about 90° C.
 12. The methodaccording to claim 11 wherein the melting point of the hydrophobicmaterial range from about 50° C. to about 80° C.
 13. The methodaccording to claim 12 wherein the melting point of the hydrophobicmaterial ranges from about 55° C. to about 75° C.
 14. The methodaccording to claim 1 wherein the hydrophobic material has a meanparticle size ranging from about 10 microns to about 200 microns. 15.The method according to claim 14 wherein the hydrophobic material has amean particle size ranging from about 30 to about 100 microns.
 16. Themethod according to claim 1 wherein the medicament is present in anamount ranging from about 25% to about 97% by weight of thepharmaceutical composition.
 17. The method according to claim 16 whereinthe medicament is present in an amount ranging from about 35% to about90% by weight of the pharmaceutical composition.
 18. The methodaccording to claim 17 wherein the medicament is present in an amountranging from about 40% to about 85% by weight of the pharmaceuticalcomposition.
 19. The method according to claim 1 wherein the hydrophobicmaterial is a wax, a fatty acid or salt thereof or a monoglyceride,diglyceride or triglyceride.
 20. The method according to claim 1 whereinthe hydrophobic material is glyceryl behenate, hydrogenated vegetableoil, stearic acid, glyceryl monostearate, glycerylpalmito stearate orcetyl alcohol.
 21. The method according to claim 1 wherein thehydrophobic material is a fatty acid having 10 to 30 carbons or saltthereof, a fatty alcohol having from 10 to 44 carbon atoms, or

R₄, R₅ and R₆ are independently lower alkyl or lower alkenyl having from10 to 29 carbon atoms and wherein at least one of R₁, R₂ and R₃ is otherthan hydrogen.
 22. The method according to claim 1 wherein themedicament is theophylline or a pharmaceutically acceptable saltthereof, ferrous sulfate, clarithromycin or divalproex.
 23. The methodaccording to claim 22 wherein the hydrophobic material is glycerylbehenate.